Only six oligonucleotide therapies have been FDA-approved due to poor cellular uptake and trafficking mechanisms not being well understood. Recent studies indicate that for a given dose of oligo, most of the material is trapped in endosomes and degraded prior to reaching the cytoplasm, thereby limiting efficacy. Despite the relative accessibility of the eye, there are several clinical trials that have been terminated for oligonucleotide-based treatments targeting age-related macular degeneration, the number-one cause of blindness in patients over 50.  Past methods for achieving oligo delivery include chemical modifications to the oligo or attaching the oligo to a nanoparticle, dendrimer, or cell-penetrating peptide. However, these methods can be toxic and unstable, and involve additional synthetic conjugation steps.<br/> <br/>We recently identified a novel method for efficient oligo delivery in cultured cells that eliminates the issue of toxicity and the need for many oligo-synthetic modifications. This method involves using fetal bovine serum (FBS), a common additive to promote cell growth, and unique oligonucleotides composed of repeating sequences of adenine or uracil and a cyanine dye.<br/> <br/>We have synthesized oligonucleotides of varied length, sequence, backbone composition, and dye labeling to identify features that contribute to efficient cellular uptake with FBS. Control experiments in denatured FBS confirm that oligo delivery is protein-mediated. We have determined that bovine serum albumin (BSA), the most abundant protein in FBS, binds to many oligos, but does not promote uptake. Oligonucleotides containing one or more photocrosslinkers were synthesized to help identify less abundant proteins associated with the oligo that contribute to the uptake process. By understanding the mechanism of this efficient cellular delivery, this system can be optimized and applied to oligo-based chemical probes and therapeutics in the future.

Probing the cellular delivery of oligonucleotides

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.